Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis-regulatory elements

Anderson, Ashlyn G.; Rogers, Brianne B.; Loupe, Jacob M.; Rodríguez-Nunez, Iván; Roberts, Sydney C.; White, Lauren M.; Brazell, J. Nicholas; Bunney, William E.; Bunney, Blynn G.; Watson, Stanley J.; Cochran, J. Nicholas; Myers, R; Rizzardi, Lindsay F.

doi:10.1016/j.xgen.2023.100263

Cited by 38 publications

(56 citation statements)

References 118 publications

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“…To further explore whether this putative regulatory region was specific to neurons, we evaluated chromatin accessibility within this locus using snATAC-seq data generated in our previous publication. 20 We found that this region was specifically accessible in both excitatory and inhibitory neurons, providing further evidence that this region functions as a neuron-specific regulatory element.…”

Section: Resultssupporting

confidence: 61%

“…49,55–57 In choosing to restrict to 1 Mb from the gene’s TSS, we are restricting to the most likely regulators of MAPT without missing long-range interactions. A description of link calls can be found in our previous publication 20 and in Methods. A total of 54,879 peak-gene links were found, including 9 MAPT -specific links ( Figure 1C, Tables 1 and S1 ).…”

Section: Resultsmentioning

confidence: 99%

“…In addition to the single nucleus multiomics data generated from cultured neurons, we also identified MAPT links from our previously published data. 20 Using nuclei from DLPFC of 7 AD and 8 control donors, we identified cell type- and disease-specific CREs and their target genes. Focusing on the MAPT locus, we expanded our original restriction of 500 kb from each gene’s TSS to 1 Mb to match our current analysis.…”

Section: Resultsmentioning

confidence: 99%

“…Here, we nominate putative cis-regulatory elements of MAPT using orthogonal genomics approaches. We integrated single nucleus RNA-seq (snRNA-seq) and ATAC-seq (snATAC-seq), from both cultured neurons and previously published DLPFC tissue 20 , to correlate chromatin accessibility with MAPT expression. We performed chromatin conformation assays (HiC and Capture-C) to determine the 3D interactions with the MAPT promoter in NPC and matched differentiated neurons, as well as pure populations of human glutamatergic and GABAergic neurons.…”

Section: Introductionmentioning

confidence: 99%

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MAPTexpression is mediated by long-range interactions withcis-regulatory elements

Rogers

Anderson

Lauzon

et al. 2023

Preprint

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Tau is encoded byMAPTand abnormal aggregates of tau are a hallmark of a group of neurodegenerative diseases called tauopathies.MAPTis lowly expressed in neural progenitor cells (NPCs), but it is more highly expressed in oligodendrocytes, astrocytes, and neurons that derive from NPCs. This expression switch at differentiation suggests thatMAPTexpression is controlled by transcription factors andcis-regulatory elements specific to these differentiated cell types, including neurons. Using three-dimensional chromatin conformation capture (Capture-C), single-nucleus multiomics (RNA-seq and ATAC-seq), and chromatin marks (H3K27ac, H3K4me1, and chromatin accessibility (DNase hypersensitivity and ATAC-seq)), we nominated 94 unique regions as candidatecis-regulatory elements forMAPTin human NPCs, NPCs differentiated to neurons, and pure inhibitory or excitatory neuron cultures. We then functionally assessed nominated regions using luciferase assays to test sufficiency for regulatory activity as well as with CRISPR inhibition experiments to assess the effect of nominated regions onMAPTexpression. We identified both proximal and distal regulatory elements forMAPTand confirmed the function for several regions, including three regions centromeric toMAPTbeyond the well-described H1/H2 haplotype inversion breakpoint.

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Section: Resultssupporting

confidence: 61%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MAPTexpression is mediated by long-range interactions withcis-regulatory elements

Rogers

Anderson

Lauzon

et al. 2023

Preprint

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“…In addition, in this paper from Pearl et al, microglia-enriched TF networks were upregulated in AD 21 . In another study, ZEB1 and MAFB were identified as candidate TFs of AD-specific cis-regulatory elements 94 . Here, we found ZEB1 to be highly active in excitatory neurons, inhibitory neurons and oligodendrocyte-precursor cells in the single-cell networks.…”

Section: Discussionmentioning

confidence: 99%

Comparative gene regulatory network analysis in Alzheimer’s disease and major depressive disorder identifies shared core regulatory circuits

Puype

Deschildre

Vermeirssen

2023

Preprint

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Major depressive disorder and Alzheimer's disease are two prevalent and devastating disorders that still lack effective treatment. Despite distinct disease phenotypes, these two disorders are characterized by similar neuroinflammatory processes. However, it is not clear to what extent these processes are shared. To compare pathways and their regulators affected in Alzheimer's disease and depression, we adopted a systems biology approach. Consensus gene regulatory networks were built from RNA-seq data with GENIE3, CLR and Lemon-Tree. The two consensus networks were functionally characterized and compared to one another. Further, single-cell gene regulatory networks were constructed with SCENIC, to further characterize the regulatory programs active in specific cell types. In both disorders, aberrations in immune mechanisms and microglial activation were found, controlled by the same transcription factors (IKZF1, IRF8, NFATC2, RUNX1, SPI1, and TAL1). These transcription factors have been implicated in Alzheimer's disease before, while only one has been associated with depression hitherto. Moreover, in Alzheimer, dysfunctions in mitochondria, the proteasome and myelination were discovered. In depression, astrocyte function, GABA receptor signaling, and transport across the blood-brain barrier were aberrated. These disrupted pathways and transcription factors should be further investigated and might be used to develop novel therapies for neuroinflammatory disorders.

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Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred

Cochran

Acosta‐Uribe

Esposito

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONGenetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations.METHODSA genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early‐onset AD study and four late‐onset AD studies.RESULTS13 variants had p<1×10−7 or p<1×10−5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14.DISCUSSIONVariants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

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Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis-regulatory elements

Cited by 38 publications

References 118 publications

MAPTexpression is mediated by long-range interactions withcis-regulatory elements

MAPTexpression is mediated by long-range interactions withcis-regulatory elements

Comparative gene regulatory network analysis in Alzheimer’s disease and major depressive disorder identifies shared core regulatory circuits

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred

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